Download 5.01.603 Epidermal Growth Factor Receptor (EGFR) Inhibitors

MEDICAL POLICY
POLICY
RELATED POLICIES
POLICY GUIDELINES
CODING
DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
APPENDIX
HISTORY
Epidermal Growth Factor Receptor (EGFR) Inhibitors
Number
5.01.603
Effective Date
October 1, 2016
Revision Date(s) 11/08/16; 09/13/16; 04/12/16; 12/08/15; 12/08/14; 12/09/13;
06/12/12; 05/10/11; 03/08/11; 09/14/10; 05/11/10; 01/12/10;
10/13/09; 07/14/09; 8/12/08;12/11/07; 04/10/07;
03/13/07;08/08/06; 02/14/06; 07/01/05
Replaces
N/A
Policy
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Small Molecule EGFR inhibitors
Erlotinib (Tarceva®) is the preferred EGFR-TK inhibitor, and may be considered medically necessary for:
 Treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
 Treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in
combination with gemcitabine
 Treatment of patients with recurrent bone cancer – chordoma
 Treatment of patients with relapsed or unresectable stage IV renal cell carcinoma with non-clear cell
histology
Gefitinib (Iressa®) may be considered medically necessary as the first-line treatment of patients with metastatic
non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19
deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
Afatinib (Gilotrif®) may be considered medically necessary for the following indications:
 Second-line therapy for patients with non-small cell lung cancer (NSCLC) with EGFR common mutations
(exon 19 deletion and exon 21 [L858R]) after a failure of erlotinib or gefitinib, unless there are patientspecific reasons why afatinib would be preferable.
 Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based
chemotherapy.
Osimertinib (Tagrisso®) may be considered medically necessary for:
 Patients 18 years of age or older with a confimed diagnosis of metastatic NSCLC.
 Patients with demonstrable disease progression on or after therapy with a Tyrosine Kinase Inhibitor
(TKI).
 Patients must test positive for EGFR T790M mutation on the FDA-approved companion diagnostic test
(cobas® EGFR Mutation test v2; Roche).
Initial treatment with the above- mentioned agents will be covered for a period of three months, with further
treatment after three months subject to approval, if there is an objective measurement of response to therapy or
lack of progression while on therapy based on (at a minimum) a chest X-ray result (or PET, CT scan).
All other uses of erlotinib, afatinib, gefitinib, and osimertinib are considered investigational.
Monoclonal Antibodies to EGFR Receptors
Cetuximab (Erbitux®) may be considered medically necessaryfor the treatment of patients with unresectable,
advanced or metastatic colorectal cancer (CRC) when all of the following criteria have been met:
 Patient expresses non-mutated (wild-type) K-RAS gene (documentation of K-RAS analysis is required)
 Patient not previously treated with panitumumab (Vectibix®)
Cetuximab (Erbitux®), in combination with radiation therapy, may be considered medically necessary for the
treatment of patients with locally or regionally advanced squamous cell carcinoma of the head and neck
(SCCHN).
Cetuximab (Erbitux®) may be considered medically necessary as single agent therapy for SCCHN patients who
have received prior radiation therapy, or have resectable locoregional recurrence or have distant metastases.
Cetuximab (Erbitux®), as a single agent or in combination with a platinum-based regimen may be considered
medically necessary for the treatment of patients with recurrent, second primary or metastatic squamous cell
carcinoma of the head and neck.
Cetuximab (Erbitux®) may be considered medically necessary for the off label treatment of patients with
recurrent or metastatic NSCLC.
Cetuximab (Erbitux®) may be considered medically necessary for the treatment of patients with recurrent or
distant metastases of squamous cell skin carcinoma.
Panitumumab (Vectibix®) may be considered medically necessary for the treatment of patients with
unresectable advanced or metastatic CRC when all of the following criteria have been met:
 Patient expresses non-mutated (wild-type) K-RAS gene (documentation of K-RAS analysis is required)
 Patient not previously treated with cetuximab (Erbitux®).
Panitumumab (Vectibix®) may be considered medically necessary for the second-line treatment of patients with
metastatic penile cancer
Use of cetuximab (Erbitux®) and panitumumab (Vectibix®) to treat other types of solid tumors and hematological
malignancies is considered investigational.
K-RAS
K-RAS mutation analysis may be considered medically necessary for predicting treatment response.
Please refer to the Policy Guidelines section for cetuximab (Erbitux®) and panitumumab (Vectibix®).
BRAF
BRAF mutation analysis may be considered medically necessary to predict nonresponse in the treatment of
metastatic colorectal cancer.
Related Policies
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5.01.517
Use of Vascular Endothelial Growth Factor Receptor (VEGF) Inhibitors and Other Angiogenesis
Inhibitors in Oncology Patients
5.01.518
Bcr-Abl Kinase Inhibitors
5.01.534
Multiple Receptor Tyrosine Kinase Inhibitors
5.01.544
Prostate Cancer Targeted Therapies
5.01.549
Off-Label Use of Drugs and Biologic Agents
Policy Guidelines
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Coding
81403
J8565
J8999
J9055
J9303
CPT
Molecular pathology procedure, Level 4, gene analysis, if performed KRAS (v-Ki-ras2 Kirsten rat
sarcoma viral oncogene) (e.g., carcinoma)
HCPCS
Gefitinib (Iressa®), oral, 250 mg
Prescription drug, oral, chemotherapeutic, NOS (includes: Erlotinib)
Injection, cetuximab, 10 mg (Erbitux)
Injection, panitumumab, 10mg (Vectibix)
Description
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Cancer is characterized by the uncontrolled growth and spread of malignant cells. Nearly 1.4 million Americans
will be diagnosed with cancer this year, and approximately 570,000 will die of the disease. The good news is
survival rates for cancer are on the rise, increasing from 50% to 64% over the last 30 years.
Conventional cytotoxic cancer chemotherapy has been one of the major medical advances realized in the last few
decades. Although directed toward certain biologic targets thought to be involved in cellular growth and proliferation,
typically they have not discriminated well between rapidly dividing normal cells (e.g., bone marrow, gastrointestinal
tract) and tumor cells, frequently resulting in toxicities. In addition, tumor responses to traditional cytotoxic cancer
chemotherapies can be unpredictable and brief.
“Targeted chemotherapies” (e.g., monoclonal antibodies, small molecule tyrosine kinase inhibitors) are the
newest therapeutic approach. These agents have been designed to interfere with Epidermal Growth Factor
Receptor proteins, which are molecular targets that have a role in tumor growth and progression. These target
proteins are typically preferentially expressed in tumor cells, thus these therapies have a higher specificity for
these cells than for normal tissues. The promise of these agents is they will provide a broader therapeutic index
with less toxicity. They may also be useful in combination with traditional cytotoxic chemotherapies,
immunotherapies or radiation to produce additive or synergistic activity without overlap in toxicity profiles.
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members
of the epidermal growth factor family (EGF-family) of extracellular protein ligands. The epidermal growth factor
receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases:
EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). EGFR plays a critical role in the
modulation of growth factor signaling. The binding of a ligand such as epidermal growth factor to EGFR induces
phosphorylation of several tyrosine residues near the C-terminal end of the EGFR protein and subsequent
activation of several tyrosine kinase signal pathways such as the MAPK, Akt and JNK pathways. The induction of
these signaling cascades enhances activities such as up regulation of RAS, RAF and mitogen-activated
phosphorylation (MAP) which develops cellular growth and invasive capacity. EGFR activation also stimulates
vascular endothelial growth factor (VEGF), which is the primary inducer of angiogenesis. As solid tumors cannot
grow without the nutritional support provided by a blood supply, angiogenesis plays a key role in progression of
these tumors. This feature makes the ErbB family of receptor proteins natural targets for development of novel
antitumor compounds.
EGFR overexpression has been identified in a variety of solid tumors (e.g., colorectal, lung, breast, kidney, liver).
Furthermore, increasing VEGF levels have been correlated with poor prognosis in many of these same
pathologies. As a result, EGFR, tyrosine kinase, and VEGF inhibitors have been developed and investigated for
the treatment of these conditions. However, much remains to be learned regarding the rational integration of
these therapies into cancer treatment regimens and methods to optimize the selection of patients most likely to
benefit.
KRAS/BRAF
The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. RAS proteins are G-proteins that cycle
between active (RAS-GTP) and inactive (RAS-GDP) forms, in response to stimulation from a cell surface receptor
such as EGFR, and act as a binary switch between the cell surface EGFR and downstream signaling pathways.
The GTPase KRas (KRAS) gene can harbor oncogenic mutations that result in a constitutively activated protein,
independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. KRAS mutations
are found in approximately 30–50% of colorectal cancer tumors and are common in other tumor types.
Serine/threonine-protein kinase B-Raf (BRAF) encodes a protein kinase, and is involved in intracellular signaling
and cell growth and is a principal downstream effector of KRAS. BRAF mutations occur in less than 10–15% of
colorectal cancers, and appear to be a marker of poor prognosis.
Recent studies have discovered that EGFR inhibition is not effective in treating tumors that have a mutation in the
K-RAS gene. It is thought that the mutant gene is in an activated state and therefore does not require signal
initiation from the EGF Receptor, which is located earlier in the signaling pathway.
However, there are still patients with KRAS wild-type tumors that do not respond to these agents, suggesting that
other factors, such as alterations in other EGFR effectors could drive resistance to anti-EGFR therapy, and
therefore, BRAF mutations are now increasingly being investigated in metastatic colorectal cancer. KRAS and
BRAF mutations are considered to be mutually exclusive.
The EGFR Inhibiting Agents Currently Available are as Follows:
Drug Name
Erlotinib (Tarceva®)
Gefitinib (Iressa®)
Osimertinib (Tagrisso®)
Cetuximab (Erbitux®)
Panitumumab (Vectibix®)
Pharmacology
How Given
FDA-Approved Uses
Small Molecules (acting inside the cell)
EGFR tyrosine
Oral (Rx)
* NSCLC, pancreatic cancer
kinase inhibitor
-NSCLC
kinase inhibitor
Oral (Rx)
NSCLC
Monoclonal Antibodies (acting at the cell membrane surface
EGFR tyrosine
IV (Clinic)
Metastatic *CRC, Head/Neck
kinase MAb
IV (Clinic)
Metastatic CRC
*NSCLC – Non-small cell lung cancer
*RCC – Renal cell carcinoma
*HCC – Hepatocellular carcinoma
*GIST – Gastrointestinal stromal tumor
*CRC – Colorectal cancer
One small molecule EGFR tyrosine kinase inhibitor is currently approved for use in the United States. Erlotinib
(Tarceva®) is approved for the treatment of patients with metastatic NSCLC. Although its mechanism of action is
not fully characterized, it is believed to selectively and reversibly inhibit the intracellular phosphorylation of EGFR
tyrosine kinase. EGFR is expressed in NSCLC, as well as numerous other solid tumors.
Two additional growth factor inhibitors differ mechanistically from these, in that they are monoclonal antibodies to
the receptors:
 Cetuximab (Erbitux®) is a recombinant chimeric monoclonal antibody that binds and inhibits human
epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on normal and tumor cells. This binding
prevents the phosphorylation and activation of kinases, resulting in the inhibition of cell growth, induction
of apoptosis, and decrease in VEGF production.
 Panitumumab (Vectibix®) is a recombinant fully human monoclonal antibody that binds and inhibits
human epidermal growth factor receptor (EGFR). It is produced in genetically engineered Chinese
Hamster ovary cells.
NCCN Compendium
The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium is based directly on the
NCCN Clinical Practice Guidelines in Oncology. The compendium lists specific panel recommendations for offlabel uses of drugs, and each recommendation is supported by a level of evidence category.
The NCCN Categories of Evidence and Consensus used in the recommendations are:
 Category 1: The recommendation is based on high level evidence (e.g. randomized controlled trials) and
there is uniform NCCN consensus.
 Category 2A: The recommendation is based on lower level evidence and there is uniform NCCN
consensus.
 Category 2B: The recommendation is based on lower level evidence and there is nonuniform NCCN
consensus (but no major disagreement).
 Category 3: The recommendation is based on any level of evidence but reflects major disagreement.
Scope
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Medical policies are systematically developed guidelines that serve as a resource for Company staff when
determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject
to the limits and conditions of the member benefit plan. Members and their providers should consult the member
benefit booklet or contact a customer services representative to determine whether there are any benefit
limitations applicable to this service or supply. This policy does not apply to Medicare Advantage.
Benefit Application
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N/A
Rationale
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Lung Cancer
Non-small cell lung cancer (NSCLC) is potentially curable if diagnosed early (Stage I or II). Unfortunately,
approximately 75% of cases are not identified until the patient has locally advanced or metastatic disease (i.e.,
Stage III or IV). Overall five year survival is only about 15%.
Two chemotherapy agents (doublet) are recommended by NCCN for first-line therapy of patients with advanced
NSCLC and good performance status (i.e., ECOG performance status 0-2). Patients with poor performance status
(i.e., 3 or 4) generally do not benefit from chemotherapy. Specifically, platinum-based regimens are
recommended. Newer agents in combination with platinum agents have generated a plateau in overall response
rate (ORR) of ≥25-35%, time to progression (TTP) of four to six months, median survival of eight to 10 months,
and one-year survival of 30-40%. None of these newer combinations have been shown to be clearly superior.
As understanding of the pathophysiology of NSCLC has improved, and because most patients with advanced
disease continue to progress following first-line chemotherapy and ultimately die within a year, newer therapies
have been developed that have demonstrated value in prolonging survival in this setting. Single-agent docetaxel
is considered the standard for comparison for second-line therapy of advanced or recurrent metastatic NSCLC. A
large randomized head-to-head study showed pemetrexed 500 mg/m2 provided similar response and survival
rates with less severe adverse events and fewer hospitalizations compared to docetaxel 75 mg/m2.
Gefitinib (Iressa®)
The safety of IRESSA is based on the data from 2462 patients with NSCLC who received IRESSA 250 mg daily
monotherapy in three randomized clinical studies (Study 2, Study 3 and Study 4). Patients with a history of
interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment or
any evidence of clinically active interstitial lung disease were excluded from these studies.
Study 2 was a randomized, multicenter, open-label trial in which 1217 patients were randomized to receive firstline treatment for metastatic NSCLC; 607 patients received IRESSA 250 mg daily and 589 patients received
carboplatin/paclitaxel. The median duration of treatment with IRESSA was 5.9 months. The study population
characteristics were: median age 57 years, age less than 65 years (73%), female (79%), Asian (100%), NSCLC
adenocarcinoma histology (100%), never smoker (94%), light ex-smoker (6%), ECOG PS 0 or 1 (90%).
Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which 1692 patients were
randomized to receive second- or third-line treatment for metastatic NSCLC; of which 1126 patients received
IRESSA 250 mg daily and 562 patients received placebo. The median duration of treatment with IRESSA was 2.9
months. The study population characteristics were: median age 62 years, age less than 65 years (60%), female
(33%), Caucasian (75%), Asian (21%), NSCLC adenocarcinoma histology (48%), never smoker (22%), ECOG PS
0 or 1 (65%), PS 2 (29%), PS 3 (5%) and two or more prior therapies (51%).
Study 4 was a randomized, multicenter, open-label trial in which 1466 patients were randomized to receive
second-line treatment for metastatic NSCLC; 729 patients received IRESSA 250 mg daily and 715 patients
received docetaxel. The median duration of treatment with IRESSA was 2.4 months. The study population
characteristics were: median age 61 years, age less than 65 years (61%), female (36%), Caucasian (79%), Asian
(21%), NSCLC adenocarcinoma histology (54%), never smoker (20%), ECOG PS 0 or 1 (88%) and two or more
prior therapies (16%).
The pooled safety database from the three randomized trials was used to evaluate for serious and uncommon
adverse drug reactions. Common adverse reactions were evaluated in Study 3. The most frequent adverse
reactions in Study 3 (incidence of >20% and greater than placebo) reported in IRESSA-treated patients were skin
reactions (47%) and diarrhea (29%). The most frequent fatal adverse reactions in IRESSA-treated patients were
respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%).
Approximately 5% of IRESSA-treated patients and 2.3% of placebo-treated patients discontinued treatment due
to an adverse event. The most frequent adverse reactions that led to discontinuation in patients treated with
IRESSA were nausea (0.5%), vomiting (0.5%) and diarrhea (0.4%).
Erlotinib (Tarceva®)
Erlotinib has proven survival benefit as a seond- or third-line therapy for the treatment of patients with
chemotherapy refractory (typically a platinum-based regimen) advanced or recurrent metastatic NSCLC
compared to basic supportive care. It has a unique and milder side effect profile compared with traditional
cytotoxics (e.g., docetaxel) recommended for use in this setting. It also offers the convenience and potential
advantages of oral versus invasive administration as a second-line therapy.
Use of cetuximab (Erbitux®), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has
the potential to increase survival in patients with advanced NSCLC. (43) A 1125 patient multinational, multicenter,
open-label, phase 3 trial, chemotherapy-naïve patients with advanced EGFR-expressing histologically or
cytologically proven Stage wet IIIB or Stage IV NSCLC were randomly assigned in a 1:1 ratio to chemotherapy
plus cetuximab (n=557) or just chemotherapy (n=568). Patients given chemotherapy plus cetuximab survived
longer than those in the chemotherapy-alone group.
A retrospective study of patients treated with first-line chemotherapy with and without erlotinib found that the
median overall survival for all patients with mutations was significantly better (>20 months, P<.001) than overall
survival for patients without mutations (10 months).
Afatinib (Gilotrif®)
One single arm phase II study and two Phase III open label studies compared afatinib with standard
chemotherapies as a first line treatment for patients with advanced or metastatic NSCLC. All patients were
newly diagnosed treatment naïve stage IIIB or IV with activating EGFR mutations. The results showed modest
efficacy of afatinib compared with standard chemotherapy. There are no comparative efficacy data for afatinib
vs. previous TKIs in common mutations (exon 19 deletion/L858R), or in preventing T790M resistance.
In the LUX-Lung 3 study, afatinib significantly prolonged PFS (11.1 months) vs. cisplatin/pemetrexed (6.9
month) (HR: 0.58 [95% CI: 0.43, 0.78]; P<0.001), but not overall survival. Median PFS was longer (13.6
months, HR: 0.47 [95% CI: 0.34, 0.65]; P<0.0001) with common EGFR mutations (Del19 and L858R). Afatinib
significantly delayed the time to deterioration for cough (HR: 0.60 [95% CI 0.41 to 0.87]; P= 0.007) and
dyspnea (HR: 0.68 [95% CI 0.50 to 0.93]; P =0.015), but not pain (HR: 0.83 [95% CI 0.62 to 1.10]; P =0.19).
However, the study included no maintenance therapy in chemotherapy group, and there was potential
investigator bias due to the awareness of new NCCN guidelines and high cross over rates.
The LUX-Lung 6 study compared efficacy and safety of afatinib to gemcitabine/cisplatin as first-line treatment in
an Asian population with EGFR positive mutations. The design and results were similar to LUX-Lung 3. Afatinib
prolonged PFS as compared to gemcitabine/cisplatin (11 months vs. 5.6 months, HR 0.28 [95% CI 0.20, 0.39];
P=0.0001). LUX-Lung 2 is a single arm, phase II study of afatinib as first and second line therapy in patients from
Taiwan and USA. Two doses of afatinib (50 mg and 40 mg) were tested in this study. The results were similar
compared to LUX-Lung 3 and LUX-Lung 6: ORR was 61%, median PFS was 10.1 month and overall survival was
24.8 months for all patients.
The most common adverse events (AE) with afatinib were diarrhea (95.2%), rash (90%), dryness, and irritation of
the skin, mucosa and nails. Although the discontinuation rate was lower in afatinib (8%) versus chemotherapy
(12%), almost half of afatinib patients required dose reduction to less than 40 mg per day and 14% discontinued
therapy due to AE. Diarrhea and rash occurred in more than 90% of patients. Serious AE included several cases
of interstitial lung disease and 4 deaths potentially due to treatment related fatal toxicity. This suggests that
afatinib may not be well tolerated, and more data are needed to ensure its safe use in a wider population. Afatinib
improved PFS and quality of life as a first-line treatment for patients with metastatic NSCLC whose tumors have
activating EGFR mutations. It is not metabolized by CYP450 enzymes as are other EGFR TKIs.
Osimertinib (Tagrisso®)
The evidence base for the approval of osimertinib consists of 2 single-arm, open-label trials (Study 1, Study 2).
The 2 studies were pooled for efficacy and adverse event outcomes because there were no substantial
differences in the patient characteristics between studies. A total of 411 patients with metastatic, EGFR T790M
mutation-positive NSCLC who had received prior EGFR TKI therapy were recruited and treated with osimertinib
80 mg until progression or unacceptable toxicity. The primary end points were ORR by RECIST criteria as
assessed by central independent review and adverse events. Secondary end points included dose-limiting
toxicity, duration of response, and PFS.
In Study 1, no patients achieved a complete response. Partial response was achieved in 115 patients, for an ORR
of 57% (95% CI, 50% to 64%). Study 2 had 2 complete responses and 126 partial responses, with an ORR of
59% (95% CI, 54% to 64%). Among responders, most patients (96%) had ongoing responses, ranging from 1.1 to
5.6 months, with a median duration of follow-up of 4.2 months in study 1 and 4 months in study 2. Pooled overall
ORR was 59% (95% CI, 54% to 64%).
Colorectal Cancer
Cetuximab has been studied as both a single agent and in combination with irinotecan in the treatment of
metastatic colorectal cancer.(28)
Pancreatic Cancer
In pancreatic cancer symptoms are typically minor until the disease has significantly progressed, and following
diagnosis the tumor is often resistant to standard anticancer therapies. These factors contribute to a high mortality
rate, with only 20% of patients surviving to one year. In patients with advanced pancreatic cancer, one-year
survival drops to approximately 10%. The current standard of therapy in unresectable, advanced, and metastatic
disease is gemcitabine.
A randomized, double-blind, placebo-controlled clinical trial added erlotinib 100 mg/day to gemcitabine in patients
with inoperable advanced pancreatic cancer. (19) The results showed modest survival benefit compared to those
receiving gemcitabine alone. There was a significant difference in overall survival [p=0.025] that favored the
erlotinib plus gemcitabine group with a hazard ratio of 0.81 [95% CI 0.67 - 0.97). The corresponding one-year
survival rates were 24% versus 17%. PFS was also significantly improved in the gemcitabine plus erlotinib
treatment group with a hazard ratio of 0.76, p=0.003. The RR [CR/PR/SD] were 58% [CR/PR=9%] and 49%
[CR/PR=8%] for the erlotinib and placebo groups, respectively. No unexpected adverse events or safety signals
were reported.
Hepatocellular Carcinoma
Hepatocellular carcinoma is the third leading cause of cancer deaths worldwide. Surgical resection and liver
transplantation are the only cures for hepatocellular carcinoma, but benefit only 15% of patients. Most cases are
fatal within one year of diagnosis. Soratenib the only pharmacotherapy option available for advanced, inoperable
hepatocellular carcinoma (HCC).
One Phase II study, N=137 patients, looked at the safety and efficacy of four week cycles of 400 mg twice daily
soratenib to patients with inoperable HCC, no prior systemic treatment and Child-Pugh A or B scores. After
independent assessment three patients (2.2%) had a partial response, eight patients (5.8%) had minor response
and 46 patients (33.6%) had stable disease for at least 16 weeks. The median time to progression was 4.2
months and median overall survival was 9.2 months. Adverse events included fatigue, diarrhea, and hand-foot
skin reaction.
One Phase III study (N=602), looked at the efficacy and safety of 400 mg soratenib twice daily compared to
placebo in patients with advanced HCC, no prior systemic treatment, ECOG 0-2 and Child-Pugh A. Primary
endpoints were median overall survival (OS) and time to symptomatic progression (TTSP). The hazard ratio for
OS was 0.69 for sorafenib versus placebo which represented 44% improvement in OS. This was the basis for
early stopping criteria. The median overall survival advantage was 10.7 months for sorafenib versus 7.9 months
for placebo. The hazard ratio for TTSP was 0.58 and median TTP was 5.5 months for sorafenib vs 2.8 months for
placebo. Adverse events incidences were similar between the two groups; however, more serious adverse events
of diarrhea and hand-foot skin reactions were seen in the sorafenib group.
The 2008 NCCN Practice Guidelines for hepatocellular carcinoma reflects the results of the Phase III study and
recommends sorafenib for patients with Child-Pugh Class A or B status as first line treatment for unresectable or
inoperable HCC and in cases of HCC metastatic disease.
2008 Update
K-RAS Mutations and Their Impact on the Clinical Effectiveness EGFR Inhibitors
Many retrospective observational studies have been performed to evaluate the contribution of mutations
downstream of the epithelial growth factor receptor (EGFR) on the efficacy of the anti-EGFR tyrosine kinase
inhibitor oncology therapies such as cetuximab, panitumumab, and gefitinib. Studies differ in design, patient
demographics, and therapeutic regimens. The majority of studies evaluating the association of K-RAS mutation
with treatment resistance conclude that wild type status is associated with a more favorable response to
treatment. Higher efficacy is often seen among tumors with wild-type K-RAS, including a higher percent and
degree of response, overall survival, and time-to-progression. However, no single outcome is consistently
statistically significant among all studies. Currently available evidence suggests that K-RAS mutation is
associated with poor response to TKI therapy, with the most evidence being for cetuximab. At this time, K-RAS
mutation status neither predicts resistance to therapy, nor does the presence of wild-type allele predict good
efficacy.
A statistically significant difference in overall response was seen in ten of 13 studies in which response was an
outcome. Response rates among K-RAS mutants ranged from 0% to 33%. Only five of 13 studies that measured
response reported any response to TKI treatment, ranging from 9.5% to 33%. No studies assessing response to
panitumumab reported any response to therapy in the K-RAS mutant group. In general, the presence of K-RAS
mutation is associated with decreased response to TKI treatment. However, studies presenting response rates of
approximately 10-30% suggest that the existence of K-RAS mutation is not the sole determinant of treatment
response. In addition, the percent of K-RAS wild-type subjects with partial or complete response is still relatively
low, ranging from 26-68%. This suggests that while K-RAS likely contributes the TKI resistance, other factors are
involved.
Seven of 15 studies assessed overall survival as an outcome. Three of these found no statistically significant
difference, and one found a difference in overall survival only among patients taking combination therapy of
cetuximab with irinotecan, while no difference in overall survival was seen in the same patients taking cetuximab
monotherapy. The remaining three found statistically significant differences in overall survival between K-RAS
mutants and K-RAS wild-type. All three assessed response to cetuximab. Comparison of the overall survival of
mutants versus wild-type found an overall median response rate of 6.9 months and 16.3 months, respectively
(p<0.001), 27.3 weeks versus 44.7 weeks, respectively (p=0.003), and 10.1 months versus 14.3 months,
respectively (p=0.026). Overall, half of the studies that measured overall survival as an outcome reported a
difference between K-RAS mutants and K-RAS wild type. The largest study performed with overall survival as an
outcome, consisting of 427 patients, found that there was no difference in overall survival between K-RAS
mutants and K-RAS wild type after treatment with panitumumab.
Eleven of 15 studies assessed progression-free-survival (PFS) or time-to-progression (TTP). Three of these
directly compared TTP or PFS between K-RAS mutants and K-RAS wild type after treatment with cetuximab
found no statistically significant difference. However, six studies directly comparing them confirmed that there was
a difference. After treatment with cetuximab, TTP for K-RAS mutants and K-RAS wild type were 10.1 weeks [95%
CI, 8 to 16 weeks] and 31.4 weeks [95% CI, 19.4 to 36 weeks], respectively. PFS was 6.9 months versus 16.3
months for mutants and wild-type, respectively (p=0.016). One study found a statistically significant difference in
progression-free survival only with cetuximab combined with irinotecan (12 weeks versus 34 weeks, p=0.016), but
not for cetuximab monotherapy. When randomized to best supportive care or best supportive care and
panitumumab, subjects with K-RAS mutations showed no difference in PFS between the two treatment arms. In
K-RAS wild-type patients, a statistically significant difference in PFS was seen (HR 0.45, 95%CI -.34-0.59). One
study with patients taking either cetuximab or panitumumab reported difference in PFS of 8.6 weeks in K-RAS
mutants versus 32 weeks in K-RAS wild type (p<0.001). Two abstracts presented at the American Society of
Clinical Oncology (ASCO) 2008 Annual Meeting evaluated the benefit of cetuximab as adjunct therapy to the
standard regimen for metastatic colorectal cancer, FOLFIRI. Both studies found that the addition of cetuximab to
standard therapy only resulted in increased median PFS in K-RAS wild-type patients. K-RAS mutants showed no
improvement in PFS. Overall, the evidence shows that K-RAS mutation is associated with shorter TTP and PFS
after treatment with TKI than K-RAS wild type. However, K-RAS mutation has been independently associated with
disease progression and this may contribute to differences in disease progression regardless of therapy.
Karapetis et al. published a study that used tissue samples from the CO.17 trial of cetuximab versus supportive
care in treating refractory advanced stage metastatic colorectal cancer patients. Five hundred seventy-two
patients were enrolled in the original clinical trial, of which tissue samples were examined for 394 patients (69%).
The remainder was unavailable for logistic reasons, or due to lack of consent. The authors observed a five-month
improvement in median overall survival (9.5 months in the cetuximab group versus 4.8 months with supportive
care) for patients with wild type K-RAS. There was no difference in survival between cetuximab and supportive
care groups for patients with K-RAS mutations.
2009 Update
The NCCN Drug Compendium
The Company recognizes indications and uses of drugs listed in the NCCN Drugs and Biologics Compendium
with Categories of Evidence and consensus of 1 and 2A as proven and Categories of Evidence and Consensus of
2B and 3 as unproven. However, Category 2B uses may be considered for coverage if they are substantiated by
provider submission of significant peer-reviewed phase 2 or phase 3 studies demonstrating treatment
effectiveness.
Schneider et al. studied the effect of various polymorphisms involving the EGFR signaling pathway in 311 patients
receiving erlotinib in NSCLC. None of 17 patients with a KRAS mutation had a tumor response, but the impact of
KRAS mutation status on survival outcomes was of borderline statistical significance. Similarly, Miller et al.
studied a series of 101 patients with bronchioalveolar carcinoma, of which no patient (zero of 18; 95% CI, 0% to
19%) whose tumor harbored a KRAS mutation responded to erlotinib.
2010 Update
This policy is updated in agreement with March 2010 NCCN Drugs and Biologics Compendium recommendations
of 1 and 2A.
2011 Update – KRAS/BRAF
Technology Assessments, Guidelines and Position Statements
The National Comprehensive Cancer Network (NCCN) guidelines (1.2011) on the treatment of colon cancer
recommend that tumor KRAS gene status testing be performed for all patients with metastatic colon cancer, on
archived specimens of primary tumor or a metastasis, at the time of diagnosis of metastatic disease. The
guidelines indicate that cetuximab and panitumumab are only indicated for patients with tumors that express the
wild-type KRAS gene (category 2A recommendation). The guidelines state that there is the option of BRAF
genotyping of tumor tissue at the diagnosis of KRAS wild-type stage IV disease, but that data regarding BRAF as
a predictor of response (or lack of) to anti-EGFR therapy remain inconclusive.
Summary
Clinical trial data show that patients with KRAS-mutated metastatic colorectal cancer do not benefit from
cetuximab or panitumumab, either as monotherapy or in combination with other treatment regimens. These data
support the use of KRAS mutation analysis of tumor DNA before considering use of cetuximab or panitumumab in
a treatment regimen. Identifying patients whose tumors express mutated KRAS will avoid exposing patients to
ineffective drugs and unnecessary drug toxicities, and expedite the use of alternative therapies. Thus, KRAS
mutation analysis may be considered medically necessary to predict nonresponse to anti-EGFR monoclonal
antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.
The data for patients with metastatic colorectal cancer and a BRAF mutation have shown consistently that a
BRAF mutation is a poor prognostic marker, as it is associated with shorter PFS and OS regardless of treatment.
The data for a BRAF mutation predicting response to anti-EGFR therapy are limited by small numbers of patients
and conflicting results among studies. However, recent data (currently unpublished) from the CRYSTAL trial
suggest that patients with KRAS wild-type/BRAF mutant tumors may respond to anti-EGFR therapy. Therefore, it
may be considered an option in the diagnosis of KRAS wild-type Stage IV disease. Nonconcurrent subgroup
analyses of BRAF mutations in patients previously randomized in the large trials in which KRAS mutations
predicted nonresponsiveness to anti-EGFR therapy will be helpful to confirm the current data available for BRAF
mutations.
2013 Update
This policy is updated in agreement with November 2013 NCCN Drugs and Biologics Compendium
recommendations of 1 and 2A. Criteria for afatinib, a new oral EGFR inhibitor, were added. A literature search
from January 1, 2013 did not identify further required changes.
2014 Update
This policy is updated with a literature search from 7/1/13 to 10/31/14. No further required changes.
2015 Update
This policy is updated with a literature search from 7/1/14 to 10/31/15. No further required changes. Revision is
planned for first quarter 2016. Reviewed by the Pharmacy and Therapeutics committee November 19, 2015.
2016 Update
This policy was updated to include a new kinase inhibitor, osimertinib (Tagrisso®) used for the treatment of
NSCLC. A revised indication for Erlotinib (Tarceva®) used for the treatment of NSCLC was added.
Consideration of Age
The age for which Osimertinib (Tagrisso®) is considered medically necessary in this policy is 18. This is because
the safety and effectiveness of Tagrisso® in pediatric patients has not been established.
References
[TOP]
1. Rusch V, Klimstra D, Venkatraman E et al. Overexpression of the epidermal growth factor receptor and its
ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not
predict tumor progression. Clin Cancer Res 1997; 3:515-522.
2. Arteaga C. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to
therapeutic target in human neoplasia: J Clin Onc. 2001; 19:32s-40s,
3. Miller V, Johnson H. Krug LM et al. Pilot trial of the epidermal growth factor receptor tyrosine kinase
inhibitor gefitinib plus carboplatin and paclitaxel in patients with stage IIIB or IV non-small cell lung cancer.
J. Clin. Oncol. 2003; 21:2094-2100.
4. Herbst RS, Prager D, Hermann R et al. TRIBUTE-A: Phase III trial of erlotinib HCl (OSI-774) combined
with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer. Proc Am Soc
Clin Oncol. 2004; 23: ASCO Abstract #7011.
5. Gatzemeier U, Pluzanska A, Szczesna A et al. Results of a phase 3 trial of erlotinib (OSI-774) combined
with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer. Proc Am Soc
Clin Oncol. 2004; 23:ASCO Abstract #7010.
6. Tarceva (erlotinib) prescribing information. Genentech Inc.; South San Francisco, CA; 2004.
7. Shepherd FA, Pereira J, Ciuleanu TE et al. A randomized placebo-controlled trial of erlotinib in patients
with advanced non-small cell lung cancer (NSCLC) following failure of 1st or 2nd line chemotherapy.
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO); New
Orleans, LA; June 5-8, 2004. ASCO Abstract #7022.
8. Perez-Soler, R, Chachoua A, Hammond LA et al. Determinants of tumor response and survival with
erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004; 22:3238-3247.
9. Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin
Cancer Res. 2004; 10 (Suppl):4238s-4240s.
10. Fukoka M, Yano S, Giaccone G et al. Final results from a phase II trial of ZD 1839 (Iressa) for patients
with advanced non-small lung cell cancer (IDEAL1). J Clin Oncol. 2003; 21:2237-2246.
11. Kris MG, Natale RB, Herbst RS et al. A phase II trail of ZD1839 (Iressa) in advanced non-small cell lung
cancer (NSCLC) patients who had failed platinum and docetaxel-based regimens (IDEAL 2). Pro Soc Clin
Oncol 2002; 21:292a
12. Johnson DH. Gefitinib (Iressa) trials in non-small cell lung cancer. Lung Cancer 2003;41:s23-s28.
13. Cella D, Bonomi A, Lloyd S et al. Reliability and validity of the Functional Assessment of Cancer Therapy
– Lung (FACT-L) quality of life instrument. Lung Cancer 1995; 12: 199-220.
14. Cella DF, Eton DT, Fairclough DL et al. What is clinical meaningful change on the functional Assessment
of Cancer Therapy_ lung Fact-L questionnaire? Result from Eastern Cooperative Oncology group
(ECOG) study 5592. J. Clin Epidemiol 2002; 55:285-295
15. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in
advanced non-small cell lung cancer: a phase III trial—INTACT-1. J Clin Oncol 2004; 22(5):777-84.
16. Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with Pacitaxel and carboplatin in
advanced non-small-cell lung cancer: a phase III trial—INTACT-2. J Clin Oncol 2004; 22(5):785-94.
17. Cappuzzo f, Gregroc V, Rossi E et al; Gefitinib in pretreated Non-small cell lung cancer (NSCLC) Analysis
of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally
advanced or metastatic NSCLC. J. Clin Oncol. 2003; 21:2658-2663
18. Hainsworth JD, Mainwaring MG, Thomas M et al. Gefitinib in the treatment of advanced, refractory nonsmall cell lung cancer: Results 124 patients. Clin. Lung cancer 2003; 4:347-355
19. Moore MJ, Goldstein D, Ham J et al. Erlotinib plus gemcitabine compared to gemcitabine alone in
patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada
Clinical Trials Group. Presented at 2005 Gastrointestinal Cancers Symposium, January 27-29, 2005;
Hollywood, FL. Abstract 77. Accessed September 2016.
20. Herbst RS, Bajorin DF, Bleiberg H et al. Clinical cancer advances 2005: Major research advances in
cancer treatment, prevention, and screening—A report from the American Society of Clinical Oncology. J
Clin Oncology. Published ahead of print on 12/02/05.
21. Motzer RJ, Murphy BA, Bacik J et al. Phase III trial of interferon alfa-2a with or without 13-cis-reinoic acid
for patients with advanced RCC. J Clin Oncol. 2000;18:2972-2980.
22. National Comprehensive Cancer Network (NCCN). https://www.nccn.org/. Accessed September 2016.
23. Capuzzo F, Varella-Garcia M, Finoccharrio G et al. Primary resistance to cetuximab therapy in EGFR
FISH-positive colorectal cancer patients. Br J Cancer. 2008;99(1): 83 – 89.
24. Goncalves A, Estyries S, Taylor-Smedra B et al. A polymorphism of EGFR extracellular domain is
associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximabbased treatment. BMC Cancer. 2008;8:129.
25. Lievre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with
advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379
26. Khambata-Ford S, Garrett CR, Meropol NJ. Expression of Epiregulin and Amphiregulin and K-RAS
mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J
Clin Oncol. 2007;25:3230-3237.
27. Di Fiore F, Blanchards F, Charbonnier F et al. Clinical relevance of KRAS mutation detection in metastatic
colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007;96(8):1166-1169.
28. De Roock W Piessevaux H, De Schutter J. KRAS wild-type state predicts survival and is associated to
early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008; 19:
508–515.
29. Lievre A, Bachet JB, Corre DL. KRAS mutation status is predictive of response to cetuximab therapy in
colorectal cancer. Cancer Res. 2006; 66(8): 3992-5
30. Amado RG, Wolf A, Peeters M. Wild-type KRAS is required for panitumumab efficacy in patients with
metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626-34.
31. Frattini M, Saletti P, Romagnani E. PTEN loss of expression predicts cetuximab efficacy in metastatic
colorectal cancer patients. Br J Cancer. 2007;97:1139-45.
32. Darwish S, Ludovini V, Pistola L et al. EGFR, KRAS, PIK3CA mutations and response to tyrosine kinase
inhibitors (TKIs) in advanced NSCLC patients. Chicago, IL: ASCO Annual Meeting; 2008. J Clin Oncol 26:
2008 (May 20 suppl; abstr 2003).
33. Merlin JL, Perkins G, Lievre A et al. Additional value of EGFR downstream signaling phosphoprotein
expression to KRAS mutation for response prediction to cetuximab in colorectal cancer (CRC). Chicago,
IL: ASCO Annual Meeting; 2008. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4126).
34. Van Cutsem E, Lang I, D’haens G et al. KRAS status and efficacy in the first-line treatment of patients
with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL
experience. Chicago, IL: ASCO Annual Meeting; 2008. J Clin Oncol 26: 2008 (May 20 suppl; abstr 2).
35. Bokemeyer C, Bondarenko I, Hartmann JT et al. KRAS status and efficacy of first-line treatment of
patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS
experience. Chicago, IL: ASCO Annual Meeting; 2008. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4000).
36. Karapetic CS, Khambata-Ford S, Jonker DJ et al. K-RAS mutations and benefit from cetuximab in
advanced colorectal cancer. N Engl J Med 2008; 359(17):1757-1765.
37. Pirker R et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer
(FLEX): an open-label randomized phase III trial. Lancet (May 2) 2009;373(9674):1525-31.
38. Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with
chemotherapy alone and in combination with Erlotinib. J Clin Oncol 2005;23 (25):423-429.
39. Schneider CP, Heigener D, Schott-von-Römer K et al. Epidermal growth factor receptor-related tumor
markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from
German centers in the TRUST study. J Thorac Oncol. 2008 Dec;3(12):1446-53.
40. Miller VA, Riely GJ, Zakowski MF, Molecular characteristics of bronchioloalveolar carcinoma and
adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008
Mar 20;26(9):1472-8.
41. ClinicalTrials.gov Accessed September 2016.
42. Khambata-Ford S, Harbison CT, Hart LL et al. Analysis of Potential Predictive Markers of Cetuximab
Benefit in BMS099, a Phase III Study of Cetuximab and First-Line Taxane/Carboplatin in Advanced Non–
Small-Cell Lung Cancer J Clin Oncol. 2010;28(6):918-27.
43. Van Cutsem E, Kohne CH, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic
colorectal cancer. N Engl J Med 2009; 360(14):1408-17.
44. Mao C, Liao RY, Qiu LX et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies
in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep 2010 [Epub ahead of print]
45. Di Nicolantonio F, Martini M, Molinari F et al. Wild-type BRAF is required for response to panitumumab or
cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26(35):5705–12.
46. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N 2009; 361(1):98–9.
47. Phillips B, Kalady M, Kim R. BRAF testing in advanced colorectal cancer: is it ready for prime time? Clin
Adv Hematol Oncol 2010; 8(6):437-44.
48. Van Cutsem E, Lang I, Folprecht G et al. Cetuximab plus FOLFIRI in the treatment of metastatic
colorectal cancer (mCRC): the influence of KRAS and BRAF biomarkers on outcome: updated data from
49.
50.
51.
52.
53.
54.
55.
56.
57.
the CRYSTAL trial. Paper presented at: American Society of Clinical Oncology 2010 Gastrointestinal
Cancers Symposium (GCS); January 22-24, 2010; Orlando, FL.
De Roock W, Claes B, Bernasconi D et al. Effects of KRAS, BRAF, NRAS and PIK3CA mutations on the
efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a
retrospective consortium analysis. Lancet Oncol 2010; 11(8):753-62.
LUX-Lung 3: Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3: a
phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with
EGFR mutations. J Clin Oncol. 2013;Jul 1. [Epub ahead of print].
LUX-Lung 2: Yang JC-H, Shih J-Y, Su W-C, et al. Afatinib for patients with lung adenocarcinoma and
epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncology.
2012a;13(5):539-548.
LUX-Lung 6: Wu YL, Zhou C, Hu CP, et al. A randomized, open-label, phase III study of afatinib versus
gemcitabine/cisplatin as first-line treatment for Asian patients with EGFR mutation-positive advanced
adenocarcinoma of the lung. Poster presented at: 49th Annual Meeting of the American Society of
Clinical Oncology (ASCO); May 31-June 4, 2013; Chicago, IL, USA. Abstract published in: J Clin Oncol.
2013(Suppl). Abstract 8016.
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with
advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre,
open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735–42.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for
European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a
multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239–46.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN
guidelines). Non-small cell lung cancer. Version 1.2015. http://www.nccn.org Accessed September 2016.
National Comprehensive Cancer Network. NCCN Drugs & Biologics Compendium. Osimertinib.
http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=432. Accessed
September 2016.
Iressa® (gefitinib) [package insert]. Cheshire, England: AstraZeneca; Published July 2015. Accessed
September 2016. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206995s000lbl.pdf
Appendix
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N/A
History
[TOP]
Date
03/08/05
10/01/05
02/14/06
06/16/06
06/21/06
08/08/06
03/13/07
04/10/07
Reason
Add to Prescription Drug Section - New Policy. Hold for notification, publish June 1, 2005
Replace Policy - Medco issue resolved, approved text being added back into Policy Statement and
Policy Guidelines. No review needed by MPC.
Replace Policy - Policy reviewed and revised per Pharmacy and Therapeutics Committee on
1/31/06. Title changed from Epidermal Growth Factor Receptor Inhibitors
Update Scope and Disclaimer - No other changes.
Update codes only. - No other changes.
Replace Policy - Policy reviewed by Pharmacy and Therapeutics Committee on 7/25/06; no
changes in policy statement; policy guidelines updated.
Replace Policy - Policy updated with literature review; references updated. Indications for Sprycel,
Nexavar, Sutent and Vectibix added to policy statement; indications for Avastin in the treatment of
ovarian cancer added as an investigational policy statement, and medically necessary in the
treatment of diabetic retinopathy. Policy Guidelines and Rationale updated.
Replace Policy - Policy reviewed by P&T March 27, 2007. Policy statement updated to clarify the
indications and criteria for medically necessary treatment with Gleevec and Sprycel. Policy
Guidelines updated.
12/11/07
08/12/08
11/11/08
07/14/09
09/15/09
10/13/09
01/12/10
05/11/10
9/14/10
03/08/11
05/10/11
06/26/12
06/29/12
12/19/12
12/09/13
12/17/14
12/08/15
03/08/16
04/12/16
09/13/16
11/08/16
Replace Policy - Policy updated with literature review; policy statement updated to include bullet
point “treatment of patients with advanced hepatocellular carcinoma (HCC)” as medically
necessary under Sorafenib (Nexavar®). Rationale and references updated to support change in
statement.
Replace Policy - Policy updated with literature search. Policy statement revised to indicate that
Erbitux may be considered medically necessary for head and neck cancer. Comment on testing for
K-RAS mutations added to Policy Guidelines. Rationale section updated, references added.
Reviewed by P&T July 24, 2008
Update Description Section - No other changes.
Replace Policy - Policy updated with literature search. Policy statements extensively revised.
References added.
Minor updates, code updates - 3rd bullet added under Tarceva’s policy statement “documentation
of susceptibility to EGFR mutation or gene amplification”. No other changes.Code S3713 added.
Replace Policy - Policy updated with literature search. Two bullets added under the Nexavar
medically necessary statement regarding gastrointestinal stromal tumors and soft-tissue sarcoma.
References added.
Replace Policy - Policy updated with literature search; no change to the policy statement. Policy
guidelines updated.
Replace Policy - Policy updated with literature search. Policy statement updated to include med
nec statement for Erbitux. Reference added. Reviewed by OAP on February 18, 2010. Reviewed
by P&T committee on March 2010.
Replace Policy - Policy statement for Erbitux updated with removal of IIIB pleural effusion/IV.
Policy guidelines for Erbitux updated with removal of guidelines under NSCLC in accordance with
NCCN guidelines. Reviewed by OAP on 8/19/10.
Replace Policy - Policy updated with literature search. BRAF, previously not addressed, may now
be considered medically necessary in colon cancer. Reviewed by OAP 02/17/11.
Replace Policy - Policy updated with the abstraction of soratenib (Nexavar®) and sinitinib (Sutent®)
which are now addressed in 5.01.534; reference to these drugs and their ability to treat renal cell
and thyroid cancers have been removed, along with associated references.
Replace policy. Literature review; no change in policy statements.
Coding update: CPT codes, 81275, 81403 and 88363 added to the policy.
Update Related Policy to add 5.01.01 and 9.03.504.
Replace policy. Policy updated in agreement with November 2013 NCCN Drugs and Biologics
Compendium recommendations of 1 and 2A. Criteria for afatinib, a new oral EGFR inhibitor, were
added. References 50 – 55 added. CPT codes 81275 and 88363 removed; they are not specific to
this policy. Deleted code S3713 removed.
Annual review. Policy updated with literature review; no change in policy statements.
Annual Review. Policy updated with literature review; no change in policy statements. Reviewed by
P & T November 2015.
Interim update. Addition of a new kinase inhibitor, osimertinib and its criteria to the policy.
Annual Review. Addition of recently revised indication for EGFR inhibitor, gefitinib and its criteria to
the policy.
Interim Update. Inclusion of a new indication for Gilotrif. Potential update of criteria for Erbitux and
Vectibix.
Minor update. A notation was added that this policy applies only to those 18 and older because
data does not support efficacy and safety in those under 18.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts
policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical
technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in
their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific
medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
©2016 Premera All Rights Reserved.
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800-722-1471 (TTY: 800-842-5357)‫بـ‬
中文 (Chinese):
本通知有重要的訊息。本通知可能有關於您透過 Premera Blue Cross 提交的
申請或保險的重要訊息。本通知內可能有重要日期。您可能需要在截止日期
之前採取行動，以保留您的健康保險或者費用補貼。您有權利免費以您的母
語得到本訊息和幫助。請撥電話 800-722-1471 (TTY: 800-842-5357)。
037338 (07-2016)
Oromoo (Cushite):
Beeksisni kun odeeffannoo barbaachisaa qaba. Beeksisti kun sagantaa
yookan karaa Premera Blue Cross tiin tajaajila keessan ilaalchisee
odeeffannoo barbaachisaa qabaachuu danda’a. Guyyaawwan murteessaa
ta’an beeksisa kana keessatti ilaalaa. Tarii kaffaltiidhaan deeggaramuuf
yookan tajaajila fayyaa keessaniif guyyaa dhumaa irratti wanti raawwattan
jiraachuu danda’a. Kaffaltii irraa bilisa haala ta’een afaan keessaniin
odeeffannoo argachuu fi deeggarsa argachuuf mirga ni qabaattu.
Lakkoofsa bilbilaa 800-722-1471 (TTY: 800-842-5357) tii bilbilaa.
Français (French):
Cet avis a d'importantes informations. Cet avis peut avoir d'importantes
informations sur votre demande ou la couverture par l'intermédiaire de
Premera Blue Cross. Le présent avis peut contenir des dates clés. Vous
devrez peut-être prendre des mesures par certains délais pour maintenir
votre couverture de santé ou d'aide avec les coûts. Vous avez le droit
d'obtenir cette information et de l’aide dans votre langue à aucun coût.
Appelez le 800-722-1471 (TTY: 800-842-5357).
Kreyòl ayisyen (Creole):
Avi sila a gen Enfòmasyon Enpòtan ladann. Avi sila a kapab genyen
enfòmasyon enpòtan konsènan aplikasyon w lan oswa konsènan kouvèti
asirans lan atravè Premera Blue Cross. Kapab genyen dat ki enpòtan nan
avi sila a. Ou ka gen pou pran kèk aksyon avan sèten dat limit pou ka
kenbe kouvèti asirans sante w la oswa pou yo ka ede w avèk depans yo.
Se dwa w pou resevwa enfòmasyon sa a ak asistans nan lang ou pale a,
san ou pa gen pou peye pou sa. Rele nan 800-722-1471
(TTY: 800-842-5357).
Deutsche (German):
Diese Benachrichtigung enthält wichtige Informationen. Diese
Benachrichtigung enthält unter Umständen wichtige Informationen
bezüglich Ihres Antrags auf Krankenversicherungsschutz durch Premera
Blue Cross. Suchen Sie nach eventuellen wichtigen Terminen in dieser
Benachrichtigung. Sie könnten bis zu bestimmten Stichtagen handeln
müssen, um Ihren Krankenversicherungsschutz oder Hilfe mit den Kosten
zu behalten. Sie haben das Recht, kostenlose Hilfe und Informationen in
Ihrer Sprache zu erhalten. Rufen Sie an unter 800-722-1471
(TTY: 800-842-5357).
Hmoob (Hmong):
Tsab ntawv tshaj xo no muaj cov ntshiab lus tseem ceeb. Tej zaum
tsab ntawv tshaj xo no muaj cov ntsiab lus tseem ceeb txog koj daim ntawv
thov kev pab los yog koj qhov kev pab cuam los ntawm Premera Blue
Cross. Tej zaum muaj cov hnub tseem ceeb uas sau rau hauv daim ntawv
no. Tej zaum koj kuj yuav tau ua qee yam uas peb kom koj ua tsis pub
dhau cov caij nyoog uas teev tseg rau hauv daim ntawv no mas koj thiaj
yuav tau txais kev pab cuam kho mob los yog kev pab them tej nqi kho mob
ntawd. Koj muaj cai kom lawv muab cov ntshiab lus no uas tau muab sau
ua koj hom lus pub dawb rau koj. Hu rau 800-722-1471
(TTY: 800-842-5357).
Iloko (Ilocano):
Daytoy a Pakdaar ket naglaon iti Napateg nga Impormasion. Daytoy a
pakdaar mabalin nga adda ket naglaon iti napateg nga impormasion
maipanggep iti apliksayonyo wenno coverage babaen iti Premera Blue
Cross. Daytoy ket mabalin dagiti importante a petsa iti daytoy a pakdaar.
Mabalin nga adda rumbeng nga aramidenyo nga addang sakbay dagiti
partikular a naituding nga aldaw tapno mapagtalinaedyo ti coverage ti
salun-atyo wenno tulong kadagiti gastos. Adda karbenganyo a mangala iti
daytoy nga impormasion ken tulong iti bukodyo a pagsasao nga awan ti
bayadanyo. Tumawag iti numero nga 800-722-1471 (TTY: 800-842-5357).
Italiano (Italian):
Questo avviso contiene informazioni importanti. Questo avviso può contenere
informazioni importanti sulla tua domanda o copertura attraverso Premera
Blue Cross. Potrebbero esserci date chiave in questo avviso. Potrebbe
essere necessario un tuo intervento entro una scadenza determinata per
consentirti di mantenere la tua copertura o sovvenzione. Hai il diritto di
ottenere queste informazioni e assistenza nella tua lingua gratuitamente.
Chiama 800-722-1471 (TTY: 800-842-5357).
日本語 (Japanese):
この通知には重要な情報が含まれています。この通知には、Premera Blue
Cross の申請または補償範囲に関する重要な情報が含まれている場合があ
ります。この通知に記載されている可能性がある重要な日付をご確認くだ
さい。健康保険や有料サポートを維持するには、特定の期日までに行動を
取らなければならない場合があります。ご希望の言語による情報とサポー
トが無料で提供されます。800-722-1471 (TTY: 800-842-5357)までお電話
ください。
Română (Romanian):
Prezenta notificare conține informații importante. Această notificare
poate conține informații importante privind cererea sau acoperirea asigurării
dumneavoastre de sănătate prin Premera Blue Cross. Pot exista date cheie
în această notificare. Este posibil să fie nevoie să acționați până la anumite
termene limită pentru a vă menține acoperirea asigurării de sănătate sau
asistența privitoare la costuri. Aveți dreptul de a obține gratuit aceste
informații și ajutor în limba dumneavoastră. Sunați la 800-722-1471
(TTY: 800-842-5357).
한국어 (Korean):
본 통지서에는 중요한 정보가 들어 있습니다. 즉 이 통지서는 귀하의 신청에
관하여 그리고 Premera Blue Cross 를 통한 커버리지에 관한 정보를
포함하고 있을 수 있습니다. 본 통지서에는 핵심이 되는 날짜들이 있을 수
있습니다. 귀하는 귀하의 건강 커버리지를 계속 유지하거나 비용을 절감하기
위해서 일정한 마감일까지 조치를 취해야 할 필요가 있을 수 있습니다.
귀하는 이러한 정보와 도움을 귀하의 언어로 비용 부담없이 얻을 수 있는
권리가 있습니다. 800-722-1471 (TTY: 800-842-5357) 로 전화하십시오.
Pусский (Russian):
Настоящее уведомление содержит важную информацию. Это
уведомление может содержать важную информацию о вашем
заявлении или страховом покрытии через Premera Blue Cross. В
настоящем уведомлении могут быть указаны ключевые даты. Вам,
возможно, потребуется принять меры к определенным предельным
срокам для сохранения страхового покрытия или помощи с расходами.
Вы имеете право на бесплатное получение этой информации и
помощь на вашем языке. Звоните по телефону 800-722-1471
(TTY: 800-842-5357).
ລາວ (Lao):
ແຈ້ ງການນ້ີ ມີຂ້ໍ ມູ ນສໍາຄັ ນ. ແຈ້ ງການນ້ີ ອາດຈະມີຂ້ໍ ມູ ນສໍາຄັ ນກ່ ຽວກັ ບຄໍາຮ້ ອງສະ
ໝັ ກ ຫື ຼ ຄວາມຄຸ້ ມຄອງປະກັ ນໄພຂອງທ່ ານຜ່ ານ Premera Blue Cross. ອາດຈະມີ
ວັ ນທີສໍາຄັ ນໃນແຈ້ ງການນີ້. ທ່ ານອາດຈະຈໍາເປັນຕ້ ອງດໍາເນີນການຕາມກໍານົ ດ
ເວລາສະເພາະເພື່ອຮັ ກສາຄວາມຄຸ້ ມຄອງປະກັ ນສຸ ຂະພາບ ຫື ຼ ຄວາມຊ່ ວຍເຫື ຼ ອເລື່ອງ
ຄ່ າໃຊ້ ຈ່ າຍຂອງທ່ ານໄວ້ . ທ່ ານມີສິດໄດ້ ຮັ ບຂ້ໍ ມູ ນນ້ີ ແລະ ຄວາມຊ່ ວຍເຫື ຼ ອເປັນພາສາ
ຂອງທ່ ານໂດຍບໍ່ເສຍຄ່ າ. ໃຫ້ ໂທຫາ 800-722-1471 (TTY: 800-842-5357).
ភាសាែខម រ (Khmer):
េសចកត ីជូនដំណឹងេនះមានព័ត៌មានយា៉ងសំខាន់។ េសចកត ីជូនដំណឹងេនះរបែហល
ជាមានព័ត៌មានយា៉ងសំខាន់អំពីទរមង់ែបបបទ ឬការរា៉ប់រងរបស់អនកតាមរយៈ
Premera Blue Cross ។ របែហលជាមាន កាលបរ ិេចឆ ទសំខាន់េនៅកនុងេសចកត ីជូន
ដំណឹងេនះ។ អន ករបែហលជារតូវការបេញច ញសមតថ ភាព ដល់កំណត់ៃថង ជាក់ចបាស់
នានា េដើមបីនឹងរកសាទុកការធានារា៉ប់រងសុខភាពរបស់អនក ឬរបាក់ជំនួយេចញៃថល ។
អន កមានសិទធិទទួ លព័ត៌មានេនះ និងជំនួយេនៅកនុងភាសារបស់អនកេដាយមិនអស
លុយេឡើយ។ សូ មទូ រស័ពទ 800-722-1471 (TTY: 800-842-5357)។
ਪੰ ਜਾਬੀ (Punjabi):
ਇਸ ਨੋਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨੋਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ਤੁਹਾਡੀ
ਕਵਰੇਜ ਅਤੇ ਅਰਜੀ ਬਾਰੇ ਮਹੱ ਤਵਪੂਰਨ ਜਾਣਕਾਰੀ ਹੋ ਸਕਦੀ ਹੈ . ਇਸ ਨੋਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ
ਹੋ ਸਕਦੀਆਂ ਹਨ. ਜੇਕਰ ਤੁਸੀ ਜਸਹਤ ਕਵਰੇਜ ਿਰੱ ਖਣੀ ਹੋਵੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ
ਇਛੁੱ ਕ ਹੋ ਤਾਂ ਤੁਹਾਨੂੰ ਅੰ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੁੱ ਕਣ ਦੀ ਲੋ ੜ ਹੋ ਸਕਦੀ ਹੈ ,ਤੁਹਾਨੂੰ
ਮੁਫ਼ਤ ਿਵੱ ਚ ਤੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵੱ ਚ ਜਾਣਕਾਰੀ ਅਤੇ ਮਦਦ ਪ੍ਰਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ
800-722-1471 (TTY: 800-842-5357).
‫( فارسی‬Farsi):
‫اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم‬. ‫اين اعالميه حاوی اطالعات مھم ميباشد‬
‫ به تاريخ ھای مھم در‬.‫ باشد‬Premera Blue Cross ‫تقاضا و يا پوشش بيمه ای شما از طريق‬
‫شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه‬. ‫اين اعالميه توجه نماييد‬
‫شما حق‬. ‫ به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد‬،‫ھای درمانی تان‬
‫ برای کسب‬.‫اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان دريافت نماييد‬
‫( تماس‬800-842-5357 ‫ تماس باشماره‬TTY ‫ )کاربران‬800-722-1471 ‫اطالعات با شماره‬
.‫برقرار نماييد‬
Polskie (Polish):
To ogłoszenie może zawierać ważne informacje. To ogłoszenie może
zawierać ważne informacje odnośnie Państwa wniosku lub zakresu
świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na
kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie
przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub
pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej
informacji we własnym języku. Zadzwońcie pod 800-722-1471
(TTY: 800-842-5357).
Português (Portuguese):
Este aviso contém informações importantes. Este aviso poderá conter
informações importantes a respeito de sua aplicação ou cobertura por meio
do Premera Blue Cross. Poderão existir datas importantes neste aviso.
Talvez seja necessário que você tome providências dentro de
determinados prazos para manter sua cobertura de saúde ou ajuda de
custos. Você tem o direito de obter esta informação e ajuda em seu idioma
e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357).
Fa’asamoa (Samoan):
Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau
ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala
atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua
atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei
fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le
aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai
i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua
atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i
ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471
(TTY: 800-842-5357).
Español (Spanish):
Este Aviso contiene información importante. Es posible que este aviso
contenga información importante acerca de su solicitud o cobertura a
través de Premera Blue Cross. Es posible que haya fechas clave en este
aviso. Es posible que deba tomar alguna medida antes de determinadas
fechas para mantener su cobertura médica o ayuda con los costos. Usted
tiene derecho a recibir esta información y ayuda en su idioma sin costo
alguno. Llame al 800-722-1471 (TTY: 800-842-5357).
Tagalog (Tagalog):
Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang
paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon
tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue
Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring
mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang
panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na
walang gastos. May karapatan ka na makakuha ng ganitong impormasyon
at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471
(TTY: 800-842-5357).
ไทย (Thai):
ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน
สุขภาพของคุณผ่าน Premera Blue Cross และอาจมีกําหนดการในประกาศนี ้ คุณอาจจะต้ อง
ดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณหรื อการช่วยเหลือที่
มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มีค่าใช้ จ่าย โทร
800-722-1471 (TTY: 800-842-5357)
Український (Ukrainian):
Це повідомлення містить важливу інформацію. Це повідомлення
може містити важливу інформацію про Ваше звернення щодо
страхувального покриття через Premera Blue Cross. Зверніть увагу на
ключові дати, які можуть бути вказані у цьому повідомленні. Існує
імовірність того, що Вам треба буде здійснити певні кроки у конкретні
кінцеві строки для того, щоб зберегти Ваше медичне страхування або
отримати фінансову допомогу. У Вас є право на отримання цієї
інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за
номером телефону 800-722-1471 (TTY: 800-842-5357).
Tiếng Việt (Vietnamese):
Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông
tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua
chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông
báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn
để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có
quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình
miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).